tbuckley/cabot-search huggingface dataset:
BIOS-04. THE ROLE OF MACHINE LEARNING, PREDICTIVE MODELING, AND DEEP LEARNING IN ASSESSING METABOLIC BIOMARKERS TO IMPROVE PROGNOSTICATION IN GLIOBLASTOMA MULTIFORME
Authors: Cathleen Kuo, Nolan Brown, Julian Gendreau
Journal: Neuro-Oncology (2023)

Abstract Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor in the United States, accounting for approximately 56.6% of all gliomas and 47.7% of all primary malignant CNS tumors. The prognosis of GBM is notably grim, with a 1-year relative survival rate of 41.4% and a 5-year survival rate of 5.8% following diagnosis. Recent efforts to identify potential therapeutic targets have utilized tumor omics data integrated with clinical information that leverages machine learning (ML) algorithms. However, there remains a paucity of studies assessing the value of these ML models as prognostic tools in GBM. A systematic search adhering to PRISMA guidelines was conducted to identify all studies describing the use of a ML algorithm involving GBM metabolic biomarkers and each algorithm's accuracy. Ten studies were included for final analysis. They were diagnostic (n = 3, 30%), prognostic (n = 6, 60%), or both (n = 1, 10%), respectively. Most studies analyzed data from multiple databases, while 50% (n = 5) included additional original samples. At least 2,536 data samples were run through a ML algorithm. 27 ML algorithms were recorded with a mean 2.8 algorithms per study. Algorithms were supervised (n = 22, 79%) or unsupervised (n = 6, 21%), and continuous (n = 21, 75%) or categorical (n = 7, 25%). The mean reported accuracy and AUC of ROC was 95.63% and 0.779, respectively. 106 metabolic markers were identified, but only EMP3 was reported in multiple studies. Many studies have identified potential biomarkers for GBM diagnosis and prognostication. These algorithms show promise; although, a consensus on even a handful of biomarkers has not been made. An integration of ML algorithms for biomarker detection combined with radiomics-based tumor imaging will be necessary to ascertain the greatest level of accuracy and precision.
MODL-48. AUTOMATING ANALYSIS OF ORGANOTYPIC BRAIN SLICE CULTURE USING MACHINE LEARNING-POWERED COMPUTER VISION
Authors: Noah Bell, Andrew Buckley, Breanna Mann, Adebimpe Adefolaju, Rajaneekar Dasari, Shawn Hingtgen, Andrew B Satterlee
Journal: Neuro-Oncology (2023)

Abstract The difficulty of image labeling and analysis poses a problem for many areas of scientific research, including the recently developed Organotypic Brain Slice Culture (OBSC) tumor characterization platform. An OBSC experiment generates dozens of images which, up to this point, had to be manually quantified. In order to increase the efficiency, consistency, and accuracy of the OBSC image analysis process, we have created a computer program which automates the analysis of OBSC images. This platform uses a number of computer vision (CV) techniques to identify objects of interest and measure their corresponding signals. For fluorescent images of single tumor spots, a straightforward thresholding algorithm divides the image into foreground and background. This automated approach substantially reduces analysis time, and the thresholding algorithm measures unusually shaped tumor spots up to 9% more accurately than previously used manual methods. Other images capture an entire plate of up to 12 OBSCs, complicating the image analysis task. A machine-learning algorithm trained on the web-based platform Biodock could identify individual OBSCs, even if they were touching each other or the sides of the wells. The ML-powered methods consistently reproduced killing curves for treatment effects on tumor tissue as well as the brain tissue substrate, and these results were obtained in much less time. By combining various CV approaches to image analysis, we have completely automated the image analysis component of our OBSC platform. This approach could be adapted to other tumor co-culture platforms.
RADT-22. STEREOTACTIC RADIOSURGERY FOR VESTIBULAR SCHWANNOMA WITH RADIOGRAPHIC BRAINSTEM COMPRESSION
Authors: Anjay Shah, Alexandra De Leo, Jonathan Li, Frank Bova, William Friedman, Robert Amdur
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND The safety of single treatment stereotactic radiosurgery (SRS) for vestibular schwannoma (VS) with radiographic evidence of brainstem compression- but without motor deficit- is controversial. Data on linac-based SRS in this setting are scarce. We address this deficit in the literature with a report of outcome of an unselected series of patients with VS with radiographic brainstem compression treated with linac SRS our institution. METHODS We included patients with unilateral VS of any size with radiographic brainstem compression at the time of SRS. All patients were without serious brainstem neurologic deficits at the time of SRS. The SRS prescription dose was 12.5 Gy in a single fraction using 6MV photon beams produced by a linear accelerator and delivered with a multiple arc technique. Inclusion in this study required at least 1 year of radiographic follow-up with magnetic resonance imaging (MRI). The primary endpoint was freedom from serious brainstem toxicity (CTCAEv5 grade &amp;gt;3); secondary endpoint was freedom from tumor enlargement considered to represent tumor progression, or any type of enlargement requiring surgical intervention. We also assessed serious cranial nerve complications, excluding hearing loss, defined as CTCAEv5 grade 3 toxicity. RESULTS Among 139 patients, the median MRI follow-up time was 5 years and the median tumor size was 2.5 cm greatest axial dimension and 5cc in volume. The median brainstem D0.03cc = 12.6 Gy, and the median brainstem V10Gy = 0.4cc. At 5 years, the actuarial freedom from serious brainstem toxicity was 100% (zero cases), and freedom from tumor enlargement, either requiring surgery or due to progression, was 90%. The rate of grade 3 facial nerve damage in patients without tumor enlargement was 0.9% (1/113). CONCLUSION Linac-based SRS as delivered in our series for VS with radiographic brainstem compression is safe and effective.
CTIM-40. EARLY RADIOGRAPHIC RESPONSE AND ENGRAFTMENT OF PHASE I FIRST-IN-HUMAN BICISTRONIC CAR T CELLS CORRELATE WITH REAL-TIME AUTOLOGOUS GBM ORGANOID CYTOLYSIS
Authors: Meghan Logun, Stephen J Bagley, Xin Wang, Daniel Zhang, Yusha Sun, Guo-li Ming, Ali Nabavizadeh, Amy Marshall, Eileen Maloney, Wei-Ting Hwang, Joseph Fraietta, Vanessa Gonzalez, Arati Desai, Linda Bagley, Elizabeth Hexner, MacLean P Nasrallah, Hongjun Song, Zev Binder, Donald M O'Rourke
Journal: Neuro-Oncology (2023)

Abstract Glioblastoma (GBM) is a highly treatment-resistant cancer, in part due to prominent inter- and intratumoral heterogeneity. To date, monovalent CAR T-cell therapies have failed to overcome this heterogeneity. Bivalent CAR-T cells may overcome this challenge by expanding the population of target-positive tumor cells. NCT05168423 is first-in-human, phase 1 dose escalation study to assess safety and feasibility of intrathecal delivery of autologous bicistronic CAR-T cells, targeting both EGFR and IL13Rα2, in patients with EGFR-amplified recurrent GBM. For each patient enrolled in this study, high-fidelity glioblastoma organoids (GBOs) are derived from tumor tissue and utilized to test the autologous CAR-T product in real-time. GBOs are co-cultured with autologous CAR-T cells and individually monitored using modified impedance spectroscopy assays over six days for quantification of real-time tumor cytolysis. CAR-T efficacy in GBOs was correlated to matched clinical trial patient outcomes, including CAR-T engraftment. To date, three patients have been treated at the initial dose level (10,000,000 CART-EGFR-IL13Rα2 cells). All three patients demonstrated tumor shrinkage on MRI obtained within 24-48hrs post-infusion. MRI changes were accompanied by significant tumor-inflammation associated neurotoxicity that resolved with steroids and IL1R blockade. Serial CSF collection for qPCR following CAR-T infusion revealed average peaks of &amp;gt;100,000 copies of CAR-T cells/μg of gDNA, comparable to CART19-treated patients. Cytotoxicity values in GBOs strongly correlated with peak CSF engraftment levels of CAR-T cells in all three patients (r = 0.998, p = 0.037). In summary, we present striking radiographic and biological responses from the first cohort of recurrent GBM patients treated with a bivalent, intrathecally delivered CAR T cell product simultaneously targeting EGFR and IL13Rα2. Potent anti-tumor activity of CART-EGFR-IL13Rα2 cells was also observed by treating patient-derived GBOs with the patients’ corresponding autologous CAR T-cell products, providing a parallel, ex vivo system for real-time prediction of CAR T-cell engraftment.
EXTH-46. SCHLAFEN11 IS A POWERFUL BIOMARKER OF CHEMOSENSITIVITY IN MEDULLOBLASTOMAS
Authors: Manabu Natsumeda, Satoshi Nakata, Junko Murai, Takahashi Haruhiko, Masayasu Okada, Jun Watanabe, Yoshihiro Tsukamoto, Kensuke Tateishi, Satoru Osuka, Eric Raabe, Celio Pouponnot, Yves Pommier, Makoto Oishi, Akiyoshi Kakita, Charles Eberhart
Journal: Neuro-Oncology (2023)

Abstract Non-biased and biased screening for prognostic factors in medulloblastomas showed that Schlafen family member 11 (SLFN11) is a powerful prognostic marker. SLFN11 is a putative DNA/RNA helicase, whose expression improves response to DNA damaging agents in some cancers, but its role in medulloblastoma has not been reported. SLFN11 protein and mRNA level were found to be expressed exclusively in WNT-activated and a proportion of SHH-activated medulloblastoma. WNT pathway activation did not acutely induce SLFN11, rather, its expression correlated with a specific hypomethylation site on the SLFN11 promoter. Genetic introduction of SLFN11 into medulloblastoma cell lines with no baseline expression dramatically increased their response to the DNA damaging agents cisplatin and SN-38 in vitro. Intracranial xenograft studies also showed markedly increased sensitivity to cisplatin after induced SLFN11 overexpression in medulloblastoma cells. In addition, CRISPR-mediated deletion of SLFN11 in a medulloblastoma cell line with high baseline expression reduced the response to chemotherapy. SLFN11 could also be upregulated pharmacologically by the histone deacetylase-inhibitor RG2833, supporting the importance of epigenetic control. Importantly, markedly increased sensitivity to cisplatin and SN-38 was seen in initially SLFN11-negative medulloblastoma cells also treated with RG2833, suggesting an approach by which more aggressive medulloblastoma subtypes might be targeted. Our findings suggest a novel mechanism for the increased chemosensitivity of some medulloblastoma subtypes linked to a specific biomarker, as well as a novel combinatorial chemotherapeutic strategy for the treatment of more aggressive medulloblastoma subtypes (Groups 3 and 4) lacking SLFN11.
TMIC-49. AUTOMATIC SEGMENTATION OF DISTINCT GLIOBLASTOMA HALLMARKS ON DIGITIZED H&amp;E SLIDES VIA DEEP LEARNING: CURATION OF A LARGE MULTI-INSTITUTIONAL COHORT
Authors: Alvaro Sandino, David S Becerra, Nelly J Sandino, Eduardo Romero, Pallavi Tiwari
Journal: Neuro-Oncology (2023)

Abstract PURPOSE Glioblastoma (GBM) is a heterogeneous brain tumor. Standard treatment constitutes surgery, chemo-radiation, and chemotherapy. After surgery, the resected tissue is analyzed under a microscope by neuropathologists to identify distinct histological hallmarks. However, visual analysis of GBM pathological features on Hematoxylin and Eosin (H&amp;E)-stained slides is subjective, time-consuming, and more importantly, requires wide expertise. We present a hierarchical deep learning-strategy to automatically segment distinct GBM hallmarks that first distinguishes necrosis (NE) from cellular tumor (CT), and subsequently, segments regions of microvascular proliferation (MV) and pseudo-palisading cell patterns (PC) within the CT region, on digitized H&amp;E slides. METHODS We employed n=541 publicly available studies including IvyGap (n=41), and TCGA (n=500). For the IvyGap cohort, expert-driven segmentations of CT, NE, MV and PC were available. We randomly employed n=21 slides from 4 patients for training, n=5 slides from 2 cases for validation, and n=2 slides from 2 cases for testing. We employed an EfficientNet model using ~600 patches of 224×224 pixels of NE and CT sampled for every slide. For semantic segmentation of MV and PC, we separately trained two EfficientNet-UNet models trained on ~200 squared-patches of 1792 and 896 pixels size, respectively. RESULTS Our hierarchical deep learning model on the IvyGap cohort achieved an accuracy of 96%, with an area under the curve (AUC) of 98% for distinguishing necrosis from non-necrotic (i.e. CT) regions. For segmenting PC and MV within the non-necrotic regions, our DL models achieve a dice score of 0.69 and 0.77, respectively. Additionally, the segmentation results for each of the pathological attributes were also generated and vetted for the TCGA cohort. CONCLUSION We developed a hierarchical model for automatic segmentation of NE, CT, and MP and PC in H&amp;E-stained Glioblastoma images which could reduce cost, time, and effort in annotating these pathological phenotypes, for quantifying the GBM micro-environment.
INNV-42. INTRA-ARTERIAL MELPHALAN FOR HISTIOCYTIC NEOPLASMS INVOLVING NEUROLOGIC, OCULAR, AND HEAD AND NECK STRUCTURES
Authors: Eli Diamond, Alexander Ramos, Jared Knopman, Julia Reilly, Julia Canestaro, Vaios Hatzoglou, Y Pierre Gobin, Andrew Garton, David Abramson, Jasmine Francis
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Histiocytic neoplasms are clonal hematopoietic disorders of myeloid lineage. Involvement of neurologic structures by histiocytic infiltration or disease-associated neurodegeneration (ND) represents a severe disease phenotype associated with morbidity and mortality. Despite recent advances with BRAF and MEK inhibitors, patients with neurohistiocytic involvement continue to demonstrate suboptimal outcomes. Intra-arterial chemotherapy (IAC) may represent an effective therapy for this disease manifestation. METHODS Patients with biopsy-proven histiocytic neoplasms involving neurologic, ocular, or head and neck structures were treated with intra-arterial melphalan delivered via selective catheterization of tumor arterial vasculature. Patients treated had refractory/persistent tumorous disease or progressive functional decline despite BRAF/MEK inhibition, or had limited disease appropriate for local therapy. Patients were evaluated for radiologic (PET or CT/MRI) response and functional neurologic response with quantified ataxia and dysarthria scales, or change in visual acuity (VA), as appropriate. Procedure-related adverse events as well as clinical and laboratory toxicities were captured. RESULTS 74 IAC treatments were administered to 17 patients, 12 with tumorous disease (6 Rosai-Dorfman disease; 3 xanthogranuloma; 3 Langerhans cell histiocytosis[LCH]; 1 Erdheim-Chester disease [ECD]), 5 with ND-LCH/ECD, and ten with disease-related impairment of VA. Patients received a range of 2-12 IAC doses. 9/12 (75%) patients with tumorous disease had complete or partial radiologic response. 4/5 patients with ND had measurable improvement in dysarthria and 2/5 had measurable improvement in ataxia. 4/10 patients had improved VA. Of all patients with clinical or radiologic response, three have experienced disease recurrence since IAC in long-term follow-up. No procedural adverse events were observed, 1 patient had neutropenia and 1 patient melphalan hypersensitivity. CONCLUSIONS IA melphalan is a safe and robustly effective treatment option for tumorous and ND histiocytic neoplasms of neurologic, ocular, and head and neck structures.
CTIM-21. T-CELL RECEPTOR REPERTOIRE ANALYSIS IN PBMCS FROM PEDIATRIC PATIENTS WITH RECURRENT MEDULLOBLASTOMA DURING ADOPTIVE CELLULAR THERAPY
Authors: Oleg Yegorov, Changlin Yang, Yanina Yegorova, Duane Mitchell
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Adoptive cellular therapy (ACT), which involves transferring tumor-specific lymphocytes, has shown promising clinical efficacy across various cancer types. However, accurately tracking these transferred cells has been challenging. To overcome this limitation, we utilized T-cell receptor (TCR) sequencing to investigate the TCR repertoire in peripheral blood mononuclear cells (PBMCs). Specifically, we examined PBMCs stimulated ex vivo using autologous dendritic cells (DCs) loaded with total tumor RNA, which we applied for infusion in pediatric patients. We also collected blood samples prior to and following immunotherapy to compare the TCR repertoire dynamics. METHODS We isolated total RNA from patient PBMCs obtained before the initiation of adoptive cellular therapy (ACT) and continued collection on a weekly basis for one month, followed by monthly collections after immunotherapy treatment. To generate cDNA, we used RACE technology with the addition of a common adapter at the 5' end. The raw sequencing data obtained was then preprocessed using MiXCR software. Subsequent TCR repertoire analysis was performed using the Immunarch R-package and VDJtools software. RESULTS&amp; CONCLUSIONS The analysis of T-cell receptor (TCR) diversity across ex vivo extended T-cell samples showed a range of 593 to 34,000 unique CDR3 clones among 28 patients with recurrent medulloblastoma. The observed range suggests that different patients exhibit distinct levels of TCR diversity. Our results revealed significant instability in the TCR repertoire within the peripheral blood during the initial 28 days after ACT for all patients. Subsequently, the regeneration was mainly driven by de novo thymic production of naïve T-cells. TCR sequencing of PBMCs stimulated with autologous DCs loaded with total tumor RNA allowed us to gain a deeper understanding of the TCR repertoire in the context of immunotherapy. This approach enabled us to track and analyze the tumor-specific T-cells in the repertoire, providing valuable insights into their behavior and response to the treatment.
CTIM-35. INB-400 PHASE 1B/2 DRUG RESISTANT IMMUNOTHERAPY WITH ACTIVATED, GENE MODIFIED ALLOGENEIC OR AUTOLOGOUS ΓΔ T CELLS IN COMBINATION WITH MAINTENANCE TEMOZOLOMIDE RECURRENT OR NEWLY DIAGNOSED GLIOBLASTOMA
Authors: Trishna Goswami, Lawrence Lamb, Kate Rochlin, Burt Nabors
Journal: Neuro-Oncology (2023)

Abstract Gamma delta (gd) T cells are innate immune cells that synergistically target cancer cells via NKG2D ligands (NKG2D-L) upregulated by chemotherapy. INB-200, a Phase 1 trial, demonstrated the safety and efficacy of autologously (auto) derived genetically modified drug resistant immunotherapy (DRI) gd T cells combined with maintenance temozolomide (TMZ) to treat newly diagnosed (ND) patients with GBM. Initiation of , a 3-arm phase 1b/2 study confirming the efficacy of the auto product in ND GBM and the safety and efficacy of an allogeneic (allo) product in both ND and relapsed GBM has begun. Arm A assesses the auto product in ND GBM patients with 1x107 cells delivered on Day 1 of cycles 1-6 along with TMZ maintenance therapy per the Stupp regimen. In the Phase 1b arm, the haploidentical allo product, will be assessed for safety in 6 relapsed GBM patients who will receive 1x107 cells in combination with 150mg/m2 of TMZ on Day 1 of every six 28-day cycles. Arm B will continue enrollment of relapsed patients following the Phase 1b and Arm C will test the safety of the allo derived product in ND, GBM patients. In Arm C, patients will receive 1x107 allo DeltEx DRI cells on Day 1 of cycles 1-6 in combination with TMZ maintenance. Cells are administered through a Rickham catheter in all arms. Primary endpoints for the Phase 1b define the RP2D and subject/ product characteristics to optimize manufacturing, while Phase 2 endpoints will determine the 12 mos OS rate for Arms A &amp; C and 9 mos OS rate for Arm B. Eligible patients are adults with IDH-wt ND or relapsed GBM with no concurrent TTF or immunotherapy, willing to place an indwelling Rickham catheter. Allo arm patients must have a haploidentical donor. Fifteen US centers will conduct study.
NCMP-26. PANCEREBELLITIS ASSOCIATED WITH CISPLATIN THERAPY IN A PATIENT WITH OROPHARYNGEAL/ NASOPHARYNGEAL SQUAMOUS CELL CARCINOMA
Authors: Yi Li, Mohammad Abualia, Jan Drappatz, Megan Mantica
Journal: Neuro-Oncology (2023)

Abstract Cisplatin, a platinum-based drug, is one of the oldest and most widely used chemotherapeutic agents. It exerts its anti-tumor effect by forming DNA inter-strand and intra-strand cross-links, resulting in lesions that eventually activate apoptotic pathways. Cisplatin remains widely used for the treatment of several solid tumors, though this is often limited by its toxicity which can affect many organ systems, including nephrotoxicity, hepatotoxicity, ototoxicity, and neurotoxicity. A dose-dependent peripheral sensory neuropathy is the most reported cisplatin-induced neurotoxicity. Central nervous system (CNS) toxicity is less common, likely due to the large molecular size of cisplatin preventing its passage through the blood-brain barrier (BBB). There have been reports of cognitive impairment, posterior reversible encephalopathy syndrome, and optic neuritis associated with cisplatin. We present a case of a 38-year-old patient who was treated with concurrent cisplatin and radiation therapy for oropharyngeal/nasopharyngeal squamous cell carcinoma, and around a month after the end of therapy, was found to have imaging findings concerning for pancerebellitis. Extensive workup into infectious causes of cerebellitis was negative. Although there are no reports in the literature of cerebellitis due to cisplatin, it could be the culprit in this case. Animal studies have shown cerebellar dysfunction occurring in the setting of cisplatin exposure. Moreover, it is thought that the drug can reach the CNS if there is a disruption of the BBB, this is supported by the fact that CNS toxicity is more seen in patients who have primary CNS neoplasia, CNS metastatic disease, radiation exposure to the head, among other mechanisms that could potentially disrupt the BBB. Thus, it is important to consider CNS adverse effects, including cerebellitis, in patients receiving cisplatin, especially among those with a potentially compromised BBB.